KUS121, a VCP modulator, has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular ATP levels
Aims: As heart failure (HF) progresses, ATP levels in myocardial cells decrease, and myocardial contractility also decreases. Inotropic drugs improve myocardial contractility but increase ATP consumption, leading to poor prognosis. Kyoto University Substance 121 (KUS121) is known to selectively inhi...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223016487 |
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| author | Shuhei Tsuji Chiharu Otani Takahiro Horie Shin Watanabe Osamu Baba Naoya Sowa Yuya Ide Asami Kashiwa Takeru Makiyama Hirohiko Imai Yasuhiro Nakashima Tomohiro Yamasaki Sijia Xu Kazuki Matsushita Keita Suzuki Fuquan Zou Eitaro Kume Koji Hasegawa Takeshi Kimura Akira Kakizuka Koh Ono |
| author_facet | Shuhei Tsuji Chiharu Otani Takahiro Horie Shin Watanabe Osamu Baba Naoya Sowa Yuya Ide Asami Kashiwa Takeru Makiyama Hirohiko Imai Yasuhiro Nakashima Tomohiro Yamasaki Sijia Xu Kazuki Matsushita Keita Suzuki Fuquan Zou Eitaro Kume Koji Hasegawa Takeshi Kimura Akira Kakizuka Koh Ono |
| author_sort | Shuhei Tsuji |
| collection | DOAJ |
| description | Aims: As heart failure (HF) progresses, ATP levels in myocardial cells decrease, and myocardial contractility also decreases. Inotropic drugs improve myocardial contractility but increase ATP consumption, leading to poor prognosis. Kyoto University Substance 121 (KUS121) is known to selectively inhibit the ATPase activity of valosin-containing protein, maintain cellular ATP levels, and manifest cytoprotective effects in several pathological conditions. The aim of this study is to determine the therapeutic effect of KUS121 on HF models. Methods and results: Cultured cell, mouse, and canine models of HF were used to examine the therapeutic effects of KUS121. The mechanism of action of KUS121 was also examined. Administration of KUS121 to a transverse aortic constriction (TAC)-induced mouse model of HF rapidly improved the left ventricular ejection fraction and improved the creatine phosphate/ATP ratio. In a canine model of high frequency-paced HF, administration of KUS121 also improved left ventricular contractility and decreased left ventricular end-diastolic pressure without increasing the heart rate. Long-term administration of KUS121 to a TAC-induced mouse model of HF suppressed cardiac hypertrophy and fibrosis. In H9C2 cells, KUS121 reduced ER stress. Finally, in experiments using primary cultured cardiomyocytes, KUS121 improved contractility and diastolic capacity without changing peak Ca2+ levels or contraction time. These effects were not accompanied by an increase in cyclic adenosine monophosphate or phosphorylation of phospholamban and ryanodine receptors. Conclusions: KUS121 ameliorated HF by a mechanism totally different from that of conventional catecholamines. We propose that KUS121 is a promising new option for the treatment of HF. |
| first_indexed | 2024-03-08T16:33:20Z |
| format | Article |
| id | doaj.art-82e21e0f2691410394d8635d08158b4a |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-08T16:33:20Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-82e21e0f2691410394d8635d08158b4a2024-01-06T04:37:34ZengElsevierBiomedicine & Pharmacotherapy0753-33222024-01-01170115850KUS121, a VCP modulator, has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular ATP levelsShuhei Tsuji0Chiharu Otani1Takahiro Horie2Shin Watanabe3Osamu Baba4Naoya Sowa5Yuya Ide6Asami Kashiwa7Takeru Makiyama8Hirohiko Imai9Yasuhiro Nakashima10Tomohiro Yamasaki11Sijia Xu12Kazuki Matsushita13Keita Suzuki14Fuquan Zou15Eitaro Kume16Koji Hasegawa17Takeshi Kimura18Akira Kakizuka19Koh Ono20Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; Preemptive Medicine and Lifestyle Disease Research Center, Kyoto University Hospital Kyoto, 606-8507, JapanDivision of Translational Research, National Hospital Organization, Kyoto Medical Center, 1-1 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, JapanDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Systems Science, Graduate School of Informatics, Kyoto University, Kyoto 606-8501, JapanDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanDepartment of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanPreemptive Medicine and Lifestyle Disease Research Center, Kyoto University Hospital Kyoto, 606-8507, JapanDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanLaboratory of Functional Biology, Kyoto University Graduate School of Biostudies and Solution Oriented Research for Science and Technology, Kyoto 606-8501, Japan; Corresponding authors.Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; Corresponding authors.Aims: As heart failure (HF) progresses, ATP levels in myocardial cells decrease, and myocardial contractility also decreases. Inotropic drugs improve myocardial contractility but increase ATP consumption, leading to poor prognosis. Kyoto University Substance 121 (KUS121) is known to selectively inhibit the ATPase activity of valosin-containing protein, maintain cellular ATP levels, and manifest cytoprotective effects in several pathological conditions. The aim of this study is to determine the therapeutic effect of KUS121 on HF models. Methods and results: Cultured cell, mouse, and canine models of HF were used to examine the therapeutic effects of KUS121. The mechanism of action of KUS121 was also examined. Administration of KUS121 to a transverse aortic constriction (TAC)-induced mouse model of HF rapidly improved the left ventricular ejection fraction and improved the creatine phosphate/ATP ratio. In a canine model of high frequency-paced HF, administration of KUS121 also improved left ventricular contractility and decreased left ventricular end-diastolic pressure without increasing the heart rate. Long-term administration of KUS121 to a TAC-induced mouse model of HF suppressed cardiac hypertrophy and fibrosis. In H9C2 cells, KUS121 reduced ER stress. Finally, in experiments using primary cultured cardiomyocytes, KUS121 improved contractility and diastolic capacity without changing peak Ca2+ levels or contraction time. These effects were not accompanied by an increase in cyclic adenosine monophosphate or phosphorylation of phospholamban and ryanodine receptors. Conclusions: KUS121 ameliorated HF by a mechanism totally different from that of conventional catecholamines. We propose that KUS121 is a promising new option for the treatment of HF.http://www.sciencedirect.com/science/article/pii/S0753332223016487Heart failureATPKUS121Therapeutic agent |
| spellingShingle | Shuhei Tsuji Chiharu Otani Takahiro Horie Shin Watanabe Osamu Baba Naoya Sowa Yuya Ide Asami Kashiwa Takeru Makiyama Hirohiko Imai Yasuhiro Nakashima Tomohiro Yamasaki Sijia Xu Kazuki Matsushita Keita Suzuki Fuquan Zou Eitaro Kume Koji Hasegawa Takeshi Kimura Akira Kakizuka Koh Ono KUS121, a VCP modulator, has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular ATP levels Biomedicine & Pharmacotherapy Heart failure ATP KUS121 Therapeutic agent |
| title | KUS121, a VCP modulator, has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular ATP levels |
| title_full | KUS121, a VCP modulator, has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular ATP levels |
| title_fullStr | KUS121, a VCP modulator, has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular ATP levels |
| title_full_unstemmed | KUS121, a VCP modulator, has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular ATP levels |
| title_short | KUS121, a VCP modulator, has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular ATP levels |
| title_sort | kus121 a vcp modulator has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular atp levels |
| topic | Heart failure ATP KUS121 Therapeutic agent |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223016487 |
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